Project Summary Alterations in the dopamine system underlie a variety of psychiatric disorders including drug addiction. In order to understand how these alterations arise, it is necessary to first understand the basic mechanisms that regulate how dopamine mediates transmission. One of the key brain regions where many drugs of abuse, including cocaine, mediate their rewarding and reinforcing properties is within the nucleus accumbens and dorsal striatum. Despite a wealth of literature examining the interaction between cocaine and the dopamine system in striatal circuits and an understanding of the cellular and molecular singling pathways of dopamine receptors, relatively little is known in regards to how the synaptic release of dopamine leads to the activation of post-synaptic receptors, where those receptors are located and how cocaine alters transmission and the synaptic activation of dopamine receptors. To address this, the current proposal will use a novel approach to examine the location and synaptic activation of D2 receptors and GABAA receptors in medium spiny neurons of the dorsal striatum and nucleus accumbens. By simultaneously imaging D2-receptors while electrophysiologically measuring their synaptic activation by dopamine the application will determine how D2-receptors encode nigrostriatal and mesolimbic dopamine signals. Additionally, the proposal aims to examine if the synaptic corelease of GABA and dopamine are differentially regulated and how cocaine exposure alters receptor synaptic activation. These experiments will test the central hypothesis that striatal dopamine transmission occurs in a point-to-point synaptic manner. The significance of this work will be to determine how dopamine receptors across striatal regions encode dopamine release and how this is altered following exposure to drugs of abuse. The proposed studies are expected to be significant in that insights in to the specific mechanisms that regulate dopamine transmission, GABA co-transmission and how they are altered by exposure to cocaine are expected to directly lead to testable hypothesis regarding the dysregulations in this system that occur as a result of chronic drug abuse and addiction.